Late-onset Tay-Sachs disease presenting with a neuromuscular phenotype-a case series.

BACKGROUND AND PURPOSE: Tay-Sachs disease is a rare and often fatal, autosomal recessive, lysosomal storage disease. Deficiency in ß-hexosaminidase leads to accumulation of GM2 ganglioside resulting in neuronal swelling and degeneration. Typical onset is in infancy with developmental regression and early death. Late-onset Tay-Sachs disease (LOTS) is extremely rare, especially in the non-Ashkenazi Jewish population, and is characterized by a more indolent presentation typically encompassing features of cerebellar and anterior horn cell dysfunction in addition to extrapyramidal and neuropsychiatric symptoms. CASES: A case series of four unrelated patients of non-Ashkenazi Jewish origin with a predominantly, and in some cases pure, neuromuscular phenotype with evidence of a motor neuronopathy on electromyography is presented. Cerebellar atrophy, reported to be a ubiquitous feature in LOTS, was absent in all patients. CONCLUSION: This case series provides evidence to support a pure neuromuscular phenotype in LOTS, which should be considered in the differential diagnosis of anterior horn cell disorders.

Premorbid cognitive functioning influences differences between self-reported cognitive difficulties and cognitive assessment in multiple sclerosis.

Cognitive difficulties are reported in up to 60% of people with MS (pwMS). There is often a discrepancy between self-reported cognitive difficulties and performance on cognitive assessments. Some of this discrepancy can be explained by depression and fatigue. Pre-MS cognitive abilities may be another important variable in explaining differences between self-reported and assessed cognitive abilities. PwMS with high estimated premorbid cognitive functioning (ePCF) may notice cognitive difficulties in daily life whilst performing within the average range on cognitive assessments. We hypothesised that, taking into account depression and fatigue, ePCF would predict (1) differences between self-reported and assessed cognitive abilities and (2) performance on cognitive assessments. We explored whether ePCF predicted (3) self-reported cognitive difficulties. Eighty-seven pwMS completed the Test of Premorbid Functioning (TOPF), the Brief International Cognitive Assessment for MS (BICAMS), self-report measures of cognitive difficulty (MS Neuropsychological Questionnaire; MSNQ), fatigue (MS Fatigue Impact Scale; MFIS) and depression (Hospital Anxiety and Depression Scale; HADS). Results revealed that, taking into account covariates, ePCF predicted (1) differences between self-reported and assessed cognitive abilities, p < .001 (model explained 29.35% of variance), and (2) performance on cognitive assessments, p < .001 (model explained 46.00% of variance), but not (3) self-reported cognitive difficulties, p = .545 (model explained 35.10% of variance). These results provide new and unique insights into predictors of the frequently observed discrepancy between self-reported and assessed cognitive abilities for pwMS. These findings have important implications for clinical practice, including the importance of exploring premorbid factors in self-reported experience of cognitive difficulties.

Word finding, prosody and social cognition in multiple sclerosis.

BACKGROUND: Impairments in speech and social cognition have been reported in people with multiple sclerosis (pwMS), although their relationships with neuropsychological outcomes and their clinical utility in MS are unclear. OBJECTIVES: To evaluate word finding, prosody and social cognition in pwMS relative to healthy controls (HC). METHODS: We recruited people with relapsing MS (RMS, n = 21), progressive MS (PMS, n = 24) and HC (n = 25) from an outpatient MS clinic. Participants completed a battery of word-finding, social cognitive, neuropsychological and clinical assessments and performed a speech task for prosodic analysis. RESULTS: Of 45 pwMS, mean (SD) age was 49.4 (9.4) years, and median (range) Expanded Disability Severity Scale score was 3.5 (1.0-6.5). Compared with HC, pwMS were older and had slower information processing speed (measured with the Symbol Digit Modalities Test, SDMT) and higher depression scores. Most speech and social cognitive measures were associated with information processing speed but not with depression. Unlike speech, social cognition consistently correlated with intelligence and memory. Visual naming test mean response time (VNT-MRT) demonstrated worse outcomes in MS versus HC (p = .034, Nagelkerke's R2  = 65.0%), and in PMS versus RMS (p = .009, Nagelkerke's R2  = 50.2%). Rapid automatised object naming demonstrated worse outcomes in MS versus HC (p = .014, Nagelkerke's R2  = 49.1%). These word-finding measures showed larger effect sizes than that of the SDMT (MS vs. HC, p = .010, Nagelkerke's R2  = 40.6%; PMS vs. RMS, p = .023, Nagelkerke's R2  = 43.5%). Prosody and social cognition did not differ between MS and HC. CONCLUSIONS: Word finding, prosody and social cognition in MS are associated with information processing speed and largely independent of mood. Impairment in visual object meaning perception is potentially a unique MS disease-related deficit that could be further explored and cautiously considered as an adjunct disability metric for MS.

Interpreting the clinical importance of the relationship between subjective fatigue and cognitive impairment in multiple sclerosis (MS): How BICAMS performance is affected by MS-related fatigue.

BACKGROUND: There is evidence that subjective fatigue can influence cognitive functioning in multiple sclerosis (MS). DeLuca et al.'s (2004) Relative Consequence Model proposes that impairments to other high-level cognitive functions, such as memory, result from the disease's effect on information processing speed. OBJECTIVE: The primary aims of the study were to investigate both 1) the relationship between subjective fatigue and cognitive functioning, as measured by the widely used Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in MS; and 2) the consequential effect of fatigue on information processing speed as predicted by the Relative Consequence Model. METHODS: 192 participants with MS attending tertiary referral MS centre completed the Modified Fatigue Impact Scale and BICAMS. RESULTS: Multiple correlation analyses determined that there were statistically significant relationships between all domains assessed by the BICAMS and levels of fatigue, such that higher levels of self-reported fatigue were associated with lower performance on information-processing, and visual and verbal learning. After controlling for information processing speed, the strength of correlation between fatigue and learning performance weakened. Linear regression analysis showed that fatigue predicted the most variance in verbal learning and 11.7% of the overall variance in BICAMS performance. CONCLUSION: Subjective fatigue and objective cognitive performance in MS are related. Caution is advised in the interpretation of BICAMS scores in cases where high levels of fatigue are present, and more detailed neuropsychological assessments may be required in order to accurately identify objective cognitive impairment independent of subjective fatigue.

Association between speech rate measures and cognitive function in people with relapsing and progressive multiple sclerosis.

Background: Cognitive impairments are well-documented in multiple sclerosis (MS), while speech impairments are often overlooked despite their significant effect on quality of life. For effective clinical management of multisystem conditions such as MS, consideration should be given to the interaction between deficits in multiple domains, such as speech and cognition. To evaluate speech rate measures of spontaneous and read speech, in people with MS and to examine the link between speech and cognition. Methods: Forty-five people with MS and 25 controls underwent an extensive cognitive battery, including executive functioning, information processing and memory tasks, and completed two speech tasks: a reading task and a picture description task, from which speech rate measures were derived. Results: The progressive MS cohort had reduced articulation (p < 0.04) and speech rate (p < 0.02) compared to controls and those with relapsing MS. Regression models also revealed information processing speed accounted for 18% to 30% of the variance of spontaneous speech rate measures, and 27% of read speech. Executive functioning accounted for a further 10% of the variance of speech rate in those with MS. Conclusions: The present study suggests that speech production is contingent on cognitive ability, with information processing speed and executive functioning linked with speech timing patterns.

Investigating the association of mood and fatigue with objective and subjective cognitive impairment in multiple sclerosis.

Discrepancies between subjective cognitive difficulties and objective measures of cognitive function in people with MS have been identified and may be related to mood and fatigue. The aim of the present study was to examine associations of depression and fatigue with discrepancies between subjective and objective cognitive functioning in pwMS. 177 participants with MS attending a University Hospital Department of Neurology MS Outpatient clinic completed the Brief International Cognitive Assessment for MS (BICAMS), MS Neuropsychological Questionnaire (MSNQ), Hospital Anxiety and Depression Scale (HADS) and Modified Fatigue Impact Scale (MFIS). To quantify the discrepancy between objective (BICAMS) and subjective (MSNQ) cognitive functioning, discrepancy scores were calculated by subtracting MSNQ z-score from composite BICAMS z-score. Based on their discrepancy score, participants were grouped as 'Underestimated', 'Overestimated' and 'Non-discrepant'. 39% of the total sample demonstrated poorer subjective cognitive functioning than their objective cognitive performance suggested ('Underestimated'). 23% of the total sample indicated lower objective scores than their subjective report suggests ('Overestimated'). 38% participants indicated relatively no discrepancy between objective and subjective cognitive measures ('Non-discrepant'). Significant differences were observed between the discrepancy groups in terms of depression and fatigue, with the 'Underestimated' group demonstrating greater levels of depression and fatigue (ps < .01). Regression analysis indicated that cognitive fatigue and depression significantly contributed to variance in subjective cognitive functioning. Our findings suggest that subjective reports of cognitive function may be influenced by depression and fatigue, emphasising the importance of cognitive, mood and fatigue screening as part of routine clinical care.

Five-year follow up of the original Irish BICAMS validation cohort.

INTRODUCTION: Cognitive impairment is common in multiple sclerosis at all stages of the condition. The natural history of cognition in multiple sclerosis has been considered to be deterioration of cognitive functioning over time. The development of the Brief International Cognitive Assessment for Multiple Sclerosis(BICAMS) has allowed standardization of a screening tool for cognitive impairment which can be easily performed in the neurology clinic. Cross-sectional and validation studies using BICAMS have been widely reported, however minimal longitudinal assessment of cognition using BICAMS has taken place to date. OBJECTIVES: The objective of this study was to evaluate the prevalence of cognitive impairment at a five-year interval in participants of an original BICAMS validation study. We will also evaluate change of the BICAMS subtests over time. MATERIALS AND METHODS: Participants of the original BICAMS validation study were invited to participate in the study. Demographic and clinical details were collected. BICAMS subtests, anxiety, depression and fatigue questionnaires were completed. RESULTS: Fifty out of the original 67 participants completed BICAMS five years post original assessment. The prevalence of cognitive impairment in this cohort with a mean age of 49 and a median EDSS of 2.5 (EDSS of 2.0 at initial BICAMS testing) remained stable five years following initial BICAMS screening assessment, X2(1)=0.36, p=.548. There was no significant difference in SDMT scores between 2014 and 2019 t(48) = 1.08, p=.15. There was an improvement in CVLT-II, t(49)=-3.03; p=.004 and BVMT-R, t(49)=-3.38; p=.001. CONCLUSIONS: This study demonstrates overall stability in the prevalence of cognitive impairment as assessed by the BICAMS. The interval of five years between assessment reduces the possibility of practice effects, although familiarity with the testing protocol may exert an influence.

Vaccine hesitancy among people with multiple sclerosis.

BACKGROUND: The current severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has raised awareness of vaccine hesitancy. Specific reasons for vaccine hesitancy among people with multiple sclerosis (pwMS) have not been fully described. Notably, pwMS may experience higher morbidity from vaccine-preventable diseases such as influenza, pneumococcal disease, and human papillomavirus (HPV)-associated warts and malignancies. Furthermore, screening for immunity against measles, mumps and rubella (MMR) is not standard practice, despite a resurgence of measles and mumps outbreaks in Europe and worldwide. We aimed to evaluate general vaccination status among pwMS to better inform vaccine practices in this cohort. METHODS: This was a prospective audit of pwMS attending an Irish tertiary referral MS centre. We designed a questionnaire that explored awareness, uptake, and hesitancy for the influenza, pneumococcal, SARS-CoV-2, HPV, and MMR vaccines. The clinician administered the questionnaire during the outpatient MS clinic. RESULTS: One-hundred-and-five pwMS participated in the audit, mean (SD) age 47.3 (12.8) years, mean MS disease duration 14.1 (9.5) years, median Expanded Disability Severity Scale (EDSS) score 2.0 (IQR 1.0-6.0), forty-nine (46.7%) were taking either maintenance immunosuppressive or immune reconstitution therapies. SARS-CoV-2 vaccine willingness among pwMS was higher (90.5 vs 60-80%) than that reported in other Western countries, and higher than that for the influenza and pneumococcal vaccines (∼80%) for which perceived unnecessity and unfamiliarity respectively were the main limiting factors. The primary reason for SARS-CoV-2 vaccine hesitancy was safety concern. PwMS who were explicitly advised by a healthcare professional to obtain the influenza vaccine were more likely to do so than those who were not (odds ratio, 8.1, 95% CI 2.8 - 23.4, p<0.001). Of pwMS currently receiving B-cell therapy (ocrelizumab/rituximab, n=12), all but one (n=11, 91.7%) have never received the pneumococcal vaccine, and a quarter (n=3) were uncertain whether to obtain this in the future. Patient-reported uptake of HPV (1.0%) and MMR (51.4%) vaccines were suboptimal. Prevalence of vaccine promotion among healthcare professionals was low (influenza vaccine, 4.8 - 32.4%; pneumococcal vaccine, 0 - 18.1%). CONCLUSIONS: Vaccine hesitancy is common (10-20%) in pwMS, consequent to insufficient knowledge and misconceptions about vaccination among pwMS and suboptimal vaccine promotion by healthcare professionals who manage pwMS. Conscientious and context-specific vaccination counselling is necessary to tackle vaccine hesitancy among pwMS, including (i) avoiding infection-associated disability accrual during MS relapses, (ii) reducing the potentially higher risk of life-threatening/treatment-refractory complications that may be observed in those who develop vaccine-preventable infections while receiving certain DMTs, and (iii) avoiding attenuated vaccine responses or delayed/interrupted DMT with early pre-treatment vaccine delivery where possible.

Postural stability is a valid and meaningful disability metric in progressive MS with potential for use in neuroprotective therapy trials.

BACKGROUND: Balance impairment is observed in up to 70% of people with MS (pwMS) and worsens with disease progression. Posturography using a force platform is the current gold standard in the measurement of balance. However, posturography has not been adequately studied or widely accepted for use as a disability outcome measure for pwMS. Importantly, the recent emergence of both successful and failed neuroprotective therapy trials in progressive MS has emphasised the need for new disability outcome measures for people with progressive MS. The main objectives of this study were to evaluate the clinical validity, reliability and feasibility of posturography as a disability metric in progressive MS. METHODS: This was a prospective cross-sectional study. We recruited 73 people with progressive MS (age 18-65 years, EDSS 3.5-6.0). Participants stood in the centre of a force platform, feet comfortably apart, under various conditions: (i) eyes open (EO), (ii) eyes closed (EC) - a single task, each lasting ninety seconds; and simultaneous EO with a cognitive test: (iii) N-Back, a three-minute test whereby participants were instructed to click the mouse when two identical letters were displayed consecutively on a screen, (iv) Sustained Attention Response Task, a five-minute test whereby participants were instructed to click the mouse for every number "1″ to "9″ except "3″ - i.e., dual-tasks. Additionally, we performed a battery of validated physical and cognitive outcome measures. Posturographic data was processed using Matlab. Statistical analysis was performed using SPSS version 26. We used multiple linear regression modelling to determine whether significant univariate correlations between posturography and clinical metrics were independent of covariates that may influence the associations seen. A two-tailed significance level of 0.05 was used. RESULTS: Of 73 participants, mean age 52.4 (8.5) years, mean MS disease duration 13.8 (10.3) years, median EDSS 5.0 (IQR 4.0-6.0), 44 (60.4%) were female. EO-Path-Length independently predicted upper extremity function (9-Hole-Peg-Test) with a larger effect size (adjusted R2=20.0%, p = 0.001) than that for walking measures (Timed 25-Foot Walk, adjusted R2=1.6%, p = 0.01; Two-Minute Walk Test, adjusted R2=7.2%, p = 0.002), while controlling for age, disease duration, height, weight, and sex. The addition of EO-Mediolateral-Displacement to the MS Functional Composite (MSFC) created a four-component z-score that increased the variance explained for quality of life (QOL) by 62.1%. Postural stability was significantly lower with mediolateral vs anteroposterior direction of sway, removal of vision, increased body weight, male sex, and fampridine use. Postural stability improved during dual-tasks compared to EO single task. Posturography detected significant worsening of balance over a single prolonged stance. CONCLUSION: Postural stability independently predicted a wide range of clinical metrics including upper extremity function, walking ability, cognition and QOL, therefore establishing construct and concurrent validity as a disability outcome measure for people with progressive MS. Additionally, posturography is a quantitative, non-invasive, quick-and-easy-to-administer, and highly sensitive device, demonstrating its high feasibility for use as a time- and resource-efficient disability metric in neuroprotective therapy trials for progressive MS.

Perceived and objective cognitive impairment in newly diagnosed versus established multiple sclerosis: impact of disease duration.

BACKGROUND: Cognitive impairment (CI) is common in multiple sclerosis (MS), including newly diagnosed MS, where it is particularly underrecognised. Determining the presence of CI in the outpatient clinic often relies on patient-reported complaints, with limited time and resources in this setting. Prior studies have shown that self-reported cognition relates poorly to formal neuropsychological testing in the MS population and correlates more with factors such as anxiety, depression and fatigue. AIMS: In this study, we assess the prevalence of perceived cognitive dysfunction in newly diagnosed MS patients and compare results with an established MS cohort. RESULTS: Thirty-nine patients with newly diagnosed MS (12 months following diagnosis) and 24 patients with an established diagnosis (3 years) were included. Similar levels of perceived and objective CI were seen in both groups. There was a strong correlation of perceived cognitive dysfunction with anxiety, mood and fatigue. Perceived cognition did not correlate with objective CI, assessed using the Brief International Cognitive Assessment in MS (BICAMS), in either group. CONCLUSIONS: Study findings add to the literature of perceived cognition in MS, in a newly diagnosed cohort. Findings are consistent with previous research using detailed neuropsychological assessments, confirming the sensitivity of BICAMS, applicable in a routine clinical setting.

Moyamoya disease and moyamoya syndrome in Ireland: patient demographics, mode of presentation and outcomes of EC-IC bypass surgery.

BACKGROUND: There are no previously published reports regarding the epidemiology and characteristics of moyamoya disease or syndrome in Ireland. AIMS: To examine patient demographics, mode of presentation and the outcomes of extracranial-intracranial bypass surgery in the treatment of moyamoya disease and syndrome in Ireland. METHODS: All patients with moyamoya disease and syndrome referred to the National Neurosurgical Centre during January 2012-January 2019 were identified through a prospective database. Demographics, clinical presentation, radiological findings, surgical procedures, postoperative complications and any strokes during follow-up were recorded. RESULTS: Twenty-one patients were identified. Sixteen underwent surgery. Median age at diagnosis was 19 years. Fifteen were female. Mode of presentation was ischaemic stroke in nine, haemodynamic TIAs in eight, haemorrhage in three and incidental in one. Sixteen patients had Moyamoya disease, whereas five patients had moyamoya syndrome. Surgery was performed on 19 hemispheres in 16 patients. The surgical procedures consisted of ten direct (STA-MCA) bypasses, five indirect bypasses and four multiple burr holes. Postoperative complications included ischaemic stroke in one patient and subdural haematoma in one patient. The median follow-up period in the surgical group was 52 months; there was one new stroke during this period. Two patients required further revascularisation following recurrent TIAs. One patient died during follow-up secondary to tumour progression associated with neurofibromatosis type 1. CONCLUSIONS: Moyamoya is rare but occurs in Caucasians in Ireland. It most commonly presents with ischaemic symptoms. Surgical intervention in the form of direct and indirect bypass is an effective treatment in the majority of cases.

An evaluation of optimal tutorial methodologies for neurology teaching at undergraduate level : Optimal tutorial methods for neurology.

AIM: We aim to determine the efficacy of an intensive week of large group tutorials in the teaching of neurology to medical students. We also look to compare teaching methods within our centre. METHODS: Students were asked to complete a questionnaire before and after large group tutorials ranking their confidence in neurology. Students from two consecutive years were studied, each using a different tutorial method. An 'intensive week' approach was then compared to a 'once a week' approach. RESULTS: Responses from pre and post the tutorial week were compared. Students reported an improvement in all domains following either method of delivering tutorials. There was no statistically significant difference between the two approaches. CONCLUSION: Large group tutorials are an effective way of delivering neurology teaching to undergraduate medical students.

Impact of obstructive sleep apnoea on cognitive function in multiple sclerosis: A longitudinal study.

Cognitive impairment (CI) and fatigue are common in people with multiple sclerosis (MS), with well-known profound effects on quality of life. Sleep disorders, including obstructive sleep apnoea (OSA), are also common in MS patients. The presence of CI has previously been shown to strongly correlate with OSA diagnosed using polysomnography in MS. Treatment of OSA has not previously been investigated as a potential modality to improve cognition in MS patients. Therefore, we sought to investigate the potential effects of OSA treatment on both cognitive function and fatigue in MS patients. Twenty-three participants with MS reporting significant fatigue were enrolled. CI was assessed by the Brief International Cognitive Assessment in MS and the 3-second Paced Auditory Serial Addition Test. All participants underwent overnight polysomnography to assess for possible OSA. Cognitive and fatigue measures were repeated in those subsequently treated for OSA and in a comparative untreated sample. Seven participants (30%) had a diagnosis of OSA based on an apnoea-hypopnea index greater than 5 per hour, with no correlation between the presence of CI and OSA. Verbal learning at follow-up assessment was seen to improve significantly in those treated for OSA, compared with those who were not treated for a sleep disorder. This small study demonstrates the potential for OSA treatment to improve verbal learning in people with MS, larger studies are indicated to further investigate the potential for cognitive and fatigue improvement in people with MS through treatment of comorbid OSA.

Short Bouts of Gait Data and Body-Worn Inertial Sensors Can Provide Reliable Measures of Spatiotemporal Gait Parameters from Bilateral Gait Data for Persons with Multiple Sclerosis.

Wearable devices equipped with inertial sensors enable objective gait assessment for persons with multiple sclerosis (MS), with potential use in ambulatory care or home and community-based assessments. However, gait data collected in non-controlled settings are often fragmented and may not provide enough information for reliable measures. This paper evaluates a novel approach to (1) determine the effects of the length of the walking task on the reliability of calculated measures and (2) identify digital biomarkers for gait assessments from fragmented data. Thirty-seven participants (37) diagnosed with relapsing-remitting MS (EDSS range 0 to 4.5) executed two trials, walking 20 m each, with inertial sensors attached to their right and left shanks. Gait events were identified from the medio-lateral angular velocity, and short bouts of gait data were extracted from each trial, with lengths varying from 3 to 9 gait cycles. Intraclass correlation coefficients (ICCs) evaluate the degree of agreement between the two trials of each participant, according to the number of gait cycles included in the analysis. Results show that short bouts of gait data, including at least six gait cycles of bilateral data, can provide reliable gait measurements for persons with MS, opening new perspectives for gait assessment using fragmented data (e.g., wearable devices, community assessments). Stride time variability and asymmetry, as well as stride velocity variability and asymmetry, should be further explored as digital biomarkers to support the monitoring of symptoms of persons with neurological diseases.

New versus old: Implications of evolving diagnostic criteria for relapsing-remitting multiple sclerosis.

The International Panel on Diagnosis of Multiple Sclerosis (MS) recently revised the 2010 McDonald criteria and made recommendations for revision, allowing for the earliest possible, accurate diagnosis of MS. For relapsing-remitting MS, positive, unmatched cerebrospinal fluid oligoclonal bands may substitute for dissemination in time. Symptomatic lesions, including brainstem and spinal cord, may demonstrate dissemination in space or in time if enhancing (with the exception of the optic nerve). Cortical and juxtacortical lesions are equivalent. In this retrospective analysis, we applied revised criteria to 250 patients previously diagnosed with relapsing-remitting MS according to 2010 criteria and assessed for change in diagnostic times. There was a significant improvement in time to diagnosis between 2010 and 2017 groups ( p < 0.01). Median time to diagnosis according to McDonald 2010 was 7.4 months, compared with 2.3 months for McDonald 2017. Use of cerebrospinal fluid results most frequently resulted in a reduction in time to diagnosis. Symptomatic gadolinium-enhancing lesions led to earliest diagnostic times.

IRAK1 Limits TLR3/4- and IFNAR-Driven IL-27 Production through a STAT1-Dependent Mechanism.

IL-27 is a cytokine exerting pleiotropic immunomodulatory effects on a broad spectrum of immune cells. Optimal IL-27 production downstream of TLR3/4 ligand stimulation relies on autocrine type I IFN signaling, defining a first and second phase in IL-27 production. This work shows that IL-1 receptor-associated kinase 1 (IRAK1) limits TLR3/4- and IFNAR-induced IL-27 production. At the mechanistic level, we identified IRAK1 as a novel regulator of STAT1, IRF1, and IRF9. We found hyperactivation of STAT1 together with increased nuclear levels of IRF1 and IRF9 in IRAK1-deficient murine macrophages compared with control cells following stimulation with LPS and poly(I:C). IRAK1-deficient human microglial cells showed higher basal levels of STAT1 and STAT2 compared with control cells. Blocking the kinase activity of TBK1/IKKε in IRAK1 knockdown human microglial cells reduced the high basal levels of STAT1/2, uncovering a TBK1/IKKε kinase-dependent mechanism controlling basal levels of STAT1/2. Stimulating IRAK1 knockdown human microglial cells with IFN-ß led to increased IL-27p28 expression compared with control cells. In IRAK1-deficient murine macrophages, increased IL-27 levels were detected by ELISA following IFN-ß stimulation compared with control macrophages together with increased nuclear levels of p-STAT1, IRF1, and IRF9. Treatment of wild-type and IRAK1-deficient murine macrophages with fludarabine similarly reduced TLR3/4-induced IL-27 cytokine levels. To our knowledge, this work represents the first report placing IRAK1 in the IFNAR pathway and identifies IRAK1 as an important regulator of STAT1, controlling IL-27 production downstream of TLR3/4 and IFNAR signaling pathways.

Encephalitis with mGluR5 antibodies: Symptoms and antibody effects.

OBJECTIVE: To report the clinical features of 11 patients with metabotropic glutamate receptor 5 (mGluR5) antibody-associated encephalitis, immunoglobulin G (IgG) subclass, and effects of the antibodies on neuronal mGluR5 clusters. METHODS: Clinical information was retrospectively obtained from referring physicians. Antibodies to mGluR5 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays. The effects of the antibodies were examined on rat hippocampal neurons with reported techniques. RESULTS: From January 2005 to May 2017, 11 patients (median age 29 years, range 6-75 years, 5 female) were identified. The main clinical features were psychiatric (10), cognitive (10), movement disorders (7), sleep dysfunction (7), and seizures (6). Median modified Rankin Scale score at the peak of the disease was 4; 4 patients required intensive care. Five patients had Hodgkin lymphoma, and 1 had small cell lung cancer. CSF showed pleocytosis (median white blood cell count 22 mm3) in all patients; brain MRI was abnormal in 5, involving limbic (1) or extralimbic (4) regions. Treatments included immunotherapy and/or oncologic therapy; at the last follow-up (median 48 months), 6 patients had complete and 5 had partial recovery. Neurologic relapse occurred in 2 patients. Antibodies were IgG1 alone (4 of 9) or in combination with IgG2 (1 of 9), IgG3 (3 of 9), or both (1). Patients' IgG caused a significant and specific decrease of cell-surface synaptic and extrasynaptic mGluR5 without altering the levels of postsynaptic density protein 95. CONCLUSIONS: Anti-mGluR5 encephalitis associates with a complex neuropsychiatric syndrome, not restricted to limbic encephalitis, and can occur without tumor. Patients respond to treatment, but relapses can occur. The antibodies have pathogenic effects altering the levels of cell-surface mGluR5.